The overall theme of this project is to identify the extent to which analogs of immunogenic peptide can influence and alter the phenotype of T helper cells. This is important not just for manipulation of the immune response, but also to deepen our understanding of the mechanisms responsible for the polarization of response towards a Th1 or Th2 phenotype. The fundamental hypothesis of this study is that the phenotype of T cells (cytokine response) will vary as a function of the stimulatory peptide ligand. In the following three aims, the goals are to identify mechanisms by which peptide shifts precursor Th0 cells in vitro (aim I), extend this information to model antigens in vivo (aim II), and apply our findings to a viral pathogen (aim III). AIM I- Analysis of the effect of partial agonists/ antagonists peptide variants on the differentiation of Th0 cells in vitro. The hypothesis underlying this aim is that analogs of immunogenic peptide can selectively activate Th0 cell functional responses and promote the differentiation into a defined Th1 or Th2 phenotype. The experimental approach will focus on three possible mechanisms by which peptide could drive the differentiation of Th0 clones which are: 1) the selective down-modulation of the IL-2 response (an anergic state), 2) the specific activation of the Th2 cytokine profile, and 3) alter the effective dose of antigen (antagonism). AIM II- Analysis of the effect of partial agonists/ antagonists peptide variants on the differentiation of Th0 cells in vivo. This aim will test the hypothesis that analogs of immunogenic peptide can selectively influence the Th response in vivo. The experimental approach will be to inject altered peptide ligands of the well-defined model antigens from aim I into inbred and TCR transgenic mice and determine the Th phenotype and precursor T cell frequency. AIM III- Analysis of a Herpes simplex-1 viral epitope and manipulation of the phenotype of the T cell response. This aim will continue to test the hypothesis that antigen can control Th response in vivo with the additional factor of influencing the response to the herpes simplex-1 pathogen. The goal of these experiments will be to apply the protocol(s) identified in aims I and II to the multi-antigenic HSV-1 pathogen. These aims are expected to accomplish our broad objectives through the use of variants of antigenic peptides to manipulate and control the Th cell response.